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Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.

ABSTRACT: BACKGROUND:High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH). METHODS:Male Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3, 7 and 14 days). After CHH exposure, skeletal muscle tissue was excised from the hind limb of rats for biochemical analysis. RESULTS:Chronic hypobaric hypoxia caused a substantial increase in protein oxidation and exhibited a greater activation of ER chaperones, glucose-regulated protein-78 (GRP-78) and protein disulphide isomerase (PDI) till 14d of CHH. Presence of oxidized proteins triggered the proteolytic systems, 20S proteasome and calpain pathway which were accompanied by a marked increase in [Ca2+]. Upregulated Akt pathway was observed upto 07d of CHH which was also linked with enhanced glycogen synthase kinase-3? (GSk-3?) expression, a negative regulator of Akt. Muscle-derived cytokines, tumor necrosis factor-? (TNF-?), interferon-? (IFN-©) and interleukin-1? (IL-1?) levels significantly increased from 07d onwards. CHH exposure also upregulated the expression of nuclear factor kappa-B (NF-?B) and E3 ligase, muscle atrophy F-box-1 (Mafbx-1/Atrogin-1) and MuRF-1 (muscle ring finger-1) on 07d and 14d. Further, severe hypoxia also lead to increase expression of ER-associated degradation (ERAD) CHOP/ GADD153, Ub-proteasome and apoptosis pathway. CONCLUSIONS:The disrupted proteostasis network was tightly coupled to degradative pathways, altered anabolic signaling, inflammation, and apoptosis under chronic hypoxia. Severe and prolonged hypoxia exposure affected the protein homeostasis which overwhelms the muscular system and tends towards skeletal muscle atrophy.

SUBMITTER: Agrawal A

PROVIDER: S-EPMC6150520 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.

Agrawal Akanksha A Rathor Richa R Kumar Ravi R Suryakumar Geetha G Ganju Lilly L

PloS one 20180921 9

<h4>Background</h4>High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH).<h4>Methods</h4>Male Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3 ...[more]

PMID: 30240405

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Project description:BackgroundHypoxemia in humans may occur during high altitude mountaineering and in patients suffering from ventilatory insufficiencies such as cardiovascular- or respiratory disease including Chronic Obstructive Pulmonary Disease (COPD). In these conditions, hypoxemia has been correlated to reduced appetite and decreased food intake. Since hypoxemia and reduced food intake intersect in various physiological and pathological conditions and both induce loss of muscle mass, we investigated whether hypoxia aggravates fasting-induced skeletal muscle atrophy and evaluated underlying protein turnover signaling.MethodsMice were kept under hypoxic (8% oxygen) or normoxic conditions (21% oxygen), or were pair-fed to the hypoxia group for 12 days. Following an additional 24 hours of fasting, muscle weight and protein turnover signaling were assessed in the gastrocnemius muscle by RT-qPCR and Western blotting.ResultsLoss of gastrocnemius muscle mass in response to fasting in the hypoxic group was increased compared to the normoxic group, but not to the pair-fed normoxic control group. Conversely, the fasting-induced increase in poly-ubiquitin conjugation, and expression of the ubiquitin 26S-proteasome E3 ligases, autophagy-lysosomal degradation-related mRNA transcripts and proteins, and markers of the integrated stress response (ISR), were attenuated in the hypoxia group compared to the pair-fed group. Mammalian target of rapamycin complex 1 (mTORC1) downstream signaling was reduced by fasting under normoxic conditions, but sustained under hypoxic conditions. Activation of AMP-activated protein kinase (AMPK) / tuberous sclerosis complex 2 (TSC2) signaling by fasting was absent, in line with retained mTORC1 activity under hypoxic conditions. Similarly, hypoxia suppressed AMPK-mediated glucocorticoid receptor (GR) signaling following fasting, which corresponded with blunted proteolytic signaling responses.ConclusionsHypoxia aggravates fasting-induced muscle wasting, and suppresses AMPK and ISR activation. Altered AMPK-mediated regulation of mTORC1 and GR may underlie aberrant protein turnover signaling and affect muscle atrophy responses in hypoxic skeletal muscle.

Project description:BackgroundChronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions.MethodsExperimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests.ResultsChronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P < 0.001; Soleus: 11.5% reduction in weight, P < 0.001) and weakness (10.0% reduction in peak-isometric torque, P < 0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P < 0.001), and incomplete strength recovery (92.3% of pre-injury levels, P < 0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P < 0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P < 0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P < 0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P < 0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy.ConclusionsChronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

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Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.

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Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.

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